BC 35 Lipogenesis Flashcards
de NOVO Lipogenesis
why
where (tissue/cell location)
When
Substrate
Anabolic reaction of syntehsis of TAGs from glycose and/or amino acids (starting substrate: AcCoA)
Two Stages: Stage 1: Denovo synthesis of FA
- high IG ratio
- mostly in liver (small amount in adipose)
in cytosol- surface of SER
Purpose: to STORE energy!
Purpose of Citrate production in deNOVO lipogenesis, and how does this happen
acCoA being made in mito matrix, but cannot get out.
Converted to CITRATE
When ATP and NADH build up duto to active TCA cycle (sat ETC/OP)
- isocitrate dehydrogenase (RL enzyme of TCA cycle) inactivated
- leads to build up of citrate (and isocitrate) which will diffuse out of mito
How to maintain high citrate levels during FA synthesis when its all being used up?
TCA Cycle priming: Tca begins to slow down from depleting the citrate
- increase in acetyl CoA (reduces PDHC)
- (increase pyruvate decarboxylase)
- PD sends AcCoA straight to OAA (prime)
Function of ATP Citrate Lyase
Requires ATP** In cytosol
Citrate to OAA & Acetl CoA
-reverse of citrate synthase
regulation: allosterically activated by citrate (feed forward)
- trans: High insulin = increased transcription of citrate lyase (slow)
Function of Acetyl CoA Carboxylase (ACC)
Requires ATP** Rate Limiting*** Cytosol
Actyl CoA +CO2 + ATP -> malonly coA + ADP+Pi
REquires biotin (Co2 transfer associated)
Regulation
allosteric:
- citrate-activator (dimer to polymer)
- long chain FA coA- inhibitor (feedback inhibition)
Phosphorylation
- high IG - dePHOS - byt insulin sig of prot phosphatase path) ACTIVE
- low IG high EP PHOS by ampK INACTIVE
Sterol dependant: gene regulation via SRE SREBP
Gene Regulation of Acetyl CoA Carboxylase
cis: SRE trans SREBP (binds to INCREASE GE)
SREBP covalently attacehd to SER (less active state)
- insulin triggers a proteolytic cleavage of SREBP from SER
- ACC gene expression increased and lipogenesis increased
Glycogen and Dietary PUFA’s (poly unsaturated fatty acids)
-prevent release of SREBP from ER (decreased ACC and decreased lipogenesis
Fatty Acid Synthase (FAS)
multifunctional enzyme, seven distinct enzymes and acyl carrier protien all on ONE pp
Cytosol (face of SER)
catalytic domains improve efficiency of FAS, growing FA chain (increasingly hydrophobic) DOES NOT leave surface of enzyme (assembly line)
AcCoA + 7Malonyl CoA + 14 NADPH–>
Palmitate + 8CoA-SH + 14 NADP (lots of CO2)
2 carbons at a time from malonyl coA (3C -but 2C donor)
-CO2 release guarantees irreversible
Two sources of NADPH for anabolic reaction
Malic Enzyme
-OAA generated by ATP Citrate Lyase reduceed to Malate using NADH
then
Malate–> Pyruvate and NADPH and CO2 (8 out of 14 needed for palmitate made here)
using Malic Enzyme (decarboxylation)
Function of Fatty Acyl CoA Synthetase (thiokinase)
in cytosol, attaches a CoA to Palmitate to form Fatty Acyl Coa (used for metabolica reactions)
it is then in activated form
Where does the glycerol phosphate come from?
LIVER
glycerol phosphate dehydrogenase (glycolysis)
converts
-F16BP-> glyceraldehyde 3P AND DHAP
-DHAP then converted to glycerol phosphate (glycerol Kinase)
glycerol Phosphate is fat backbone
both dietary and endogenous
ADIPOSE
Glycolysis leads to DHAP
-Glycerol phosphate dehydrogenase coverts DHAP to glycerol phosphate
- mainly used in adipo tissue to resynthesize TAGs
- dietary ONLY to make tags, not endogenous
DHAP is generated AFTER glycolysis RL step
stage II lipogenesis
synthesis of TAG
3FA + glycerol P –> TAG–> VLDL –> blood
Pos 1 is saturated FA
Pos 2 is PUFA
Pos 3 is either
-fluid state in humans
FED STATE
connection of lipogenesis to other paths
FA SYNTHESIS
glycolysis-PDHC and TCA–> citrate and ac CoA
HMG shunt and malic enzyme: NADPH
TAG synthesis:
DHAP makes glycerol P
Regulation of FA synthesis
high IG
-increased syntehsis of enz(ACC viw SREBP)
low IG and PUFAs: decrease synthesis
-olive corn soy walnuts all rich in PUFAs
answer Q’s at end of lecture
answer them
